Pyridones useful as inhibitors of kinases

ABSTRACT

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

CROSS REFERENCE TO RELATED APPLICATIONS

This present application claims the benefit, under 35 U.S.C. §119, toU.S. Provisional Application No. 60/712,642, filed Aug. 29, 2005; theentire disclosure of which is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofprotein kinases. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders. Theinvention also provides processes for preparing the compounds of theinvention.

BACKGROUND OF THE INVENTION

The Tec family of non-receptor tyrosine kinases plays a central role insignaling through antigen-receptors such as the TCR, BCR and Fcεreceptors (reviewed in Miller A, et al. Current Opinion in Immunology14;331-340 (2002). Tec family kinases are essential for T cellactivation. Three members of the Tec family, Itk, Rlk and Tec, areactivated downstream of antigen receptor engagement in T cells andtransmit signals to downstream effectors, including PLC-γ. Deletion ofItk in mice results in reduced T cell receptor (TCR)-inducedproliferation and secretion of the cytokines IL-2, IL-4, IL-5, IL-10 andIFN-γ. (Schaeffer et al, Science 284; 638-641 (1999)), Fowell et al,Immunity 11;399-409 (1999), Schaeffer et al Nature Immunology 2,12;1183-1188 (2001))). The immunological symptoms of allergic asthma areattenuated in Itk−/− mice. Lung inflammation, eosinophil infiltrationand mucous production are drastically reduced in Itk−/− mice in responseto challenge with the allergen OVA (Mueller et al, Journal of Immunology170: 5056-5063 (2003)). Itk has also been implicated in atopicdermatitis. This gene has been reported to be more highly expressed inperipheral blood T cells from patients with moderate and/or severeatopic dermatitis than in controls or patients with mild atopicdermatitis (Matsumoto et al, International archives of Allergy andImmunology 129; 327-340 (2002)).

Tec family kinases are also essential for B cell development andactivation. Patients with mutations in Btk have a profound block in Bcell development, resulting in the almost complete absence of Blymphocytes and plasma cells, severely reduced Ig levels and a profoundinhibition of humoral response to recall antigens (reviewed in Vihinenet al Frontiers in Bioscience 5:d917-928).

Tec kinases also play a role in mast cell activation through thehigh-affinity IgE receptor (FcεRI). Itk and Btk are expressed in mastcells and are activated by FcεRI cross-linking (Kawakami et al, Journalof Immunology; 3556-3562 (1995)). Btk deficient murine mast cells havereduced degranulation and decreased production of proinflammatorycytokines following FcεRI cross-linking (Kawakami et al. Journal ofleukocyte biology 65:286-290). Btk deficiency also results in a decreaseof macrophage effector functions (Mukhopadhyay et al, Journal ofImmunology; 168, 2914-2921 (2002)).

Accordingly, there is a great need to develop compounds useful asinhibitors of protein kinases. In particular, it would be desirable todevelop compounds that are useful as inhibitors of Tec family (e.g.,Tec,Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases.

SUMMARY OF THE INVENTION

This invention relates to compounds and compositions useful as proteinkinase inhibitors. Compounds of this invention, and pharmaceuticallyacceptable compositions thereof, are effective as inhibitors of proteinkinases. In certain embodiments, these compounds are effective asinhibitors of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)protein kinases. These compounds have the formula I, as defined herein,or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions thereof areuseful for treating or preventing a variety of diseases, disorders orconditions, including, but not limited to, an autoimmune, inflammatory,proliferative, or hyperproliferative disease or animmunologically-mediated disease. The compounds and compositions arealso useful in methods for preventing thrombin-induced plateletaggregation. The compounds provided by this invention are also usefulfor the study of kinases in biological and pathological phenomena; thestudy of intracellular signal transduction pathways mediated by suchkinases; and the comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

1. General Description of Compounds of the Invention:

This invention provides compounds of Formula I:

or a pharmaceutically accepted salt thereof, wherein

-   -   R² is a 3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur; or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur; wherein R² is optionally        substituted with 0-5 j^(R2);    -   each R³ and R⁴ is independently H, halogen, or C₁₋₄ aliphatic        optionally substituted with 0-5 occurrences of halogen, OH,        OCH₃, OCF₃, NO₂, NH₂, CN, NHCH₃, SCH₃, N(CH₃)₂, or C₁₋₂aliphatic        optionally substituted 0-5 times with F; this definition of R³        and R⁴ includes perfluorinated methyl and ethyl;    -   Q is 5-membered heteroaryl containing 1-4 nitrogen atoms,        wherein one of the nitrogen atoms is NH; each Q is optionally        substituted with 0-3 J^(Q) and is optionally fused to ring Q¹;    -   Q¹ is a 5-6 membered aryl or heteroaryl ring containing up to 3        heteroatoms selected from O, N, and S; each Q¹ is optionally        substituted with 0-5 J^(Q);    -   J^(R2) and J^(Q) are each independently halogen, —NO₂, —CN, C₁₋₆        aliphatic, C₆₋₁₀aryl, —C₁₋₆alkyl-(C₆₋₁₀aryl), 5-12 membered        heteroaryl, —C₁₋₆alkyl-(5-12 membered heteroaryl), 3-12 membered        heterocyclyl, —C₁₋₆alkyl-(3-12 membered heterocyclyl),        C₃₋₁₀cycloaliphatic, —C₁₋₆alkyl-(C₃₋₁₀cycloaliphatic), —OR^(o),        —SR^(o), —N(R^(o))₂, —(C₁₋₆alkyl)-OR^(o),        —(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o), —NR^(o)C(O)R^(o),        —NR^(o)C(S)R^(o), —NR^(o)C(O)N(R^(o))₂, —NR^(o)C(S)N(R^(o))₂,        —NR^(o)CO₂R^(o), —NR^(o)NR^(o)C(O)R^(o),        —NR^(o)NR^(o)C(O)N(R^(o))₂, —NR^(o)NR^(o)CO₂R^(o),        —C(O)C(O)R^(o), —C(O)CH₂C(O)R^(o), —CO₂R^(o), —C(O)R^(o),        —C(S)R^(o), —C(O)N(R^(o))₂, —C(S)N(R^(o))₂, —OC(O)N(R^(o))₂,        —OC(O)R^(o), —C(O)N(OR^(o))R^(o), —C(NOR^(o))R^(o), —S(O)₂R^(o),        —S(O)₃R^(o), —SO₂N(R^(o))₂, —S(O)R^(o), —NR^(o)SO₂N(R^(o))₂,        —NR^(o)SO₂R^(o), —N(OR^(o))R^(o), —C(═NH)-N(R^(o))₂,        —P(O)₂R^(o), —PO(R^(o))₂, —OPO(R^(o))₂, ═O, ═S, ═NNHR^(o),        ═NN(R^(o))₂, ═NNHC(O)R^(o), ═NNHCO₂(C₁₋₆alkyl),        ═NNHSO₂(C₁₋₆alkyl), ═NOH, ═NR^(o); or C₁₋₁₀ alkylidene chain,        wherein up to three methylene units of the chain are        independently replaced by —NR^(o)—, —O—, —S—, —SO—, SO₂—, or        —CO—; wherein each J^(R2) and J^(Q) is independently and        optionally substituted with 0-5 R^(X);    -   each R^(X) is independently H, halogen, NO₂, CN, NH₂,        NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, OH, O(C₁₋₄aliphatic),        O(C₁₋₄haloaliphatic), CO(C₁₋₄aliphatic), CO₂H,        CO₂(C₁₋₄aliphatic), C₁₋₆aliphatic, C₁₋₄haloaliphatic, phenyl,        —O(Ph), 5-6 membered heteroaryl, C₃₋₈cycloaliphatic, 5-8        membered heterocyclyl, —C₁₋₆aliphatic—(Ph), —C₁₋₆alkyl-(5-6        membered heteroaryl), —C₁₋₆alkyl-(C₃₋₈cycloaliphatic),        —C₁₋₆alkyl-(5-8 membered heterocyclyl), or C₁₋₁₀alkylidene chain        wherein up to 2 methylene units of the chain are optionally        replaced by O, N, or S; wherein each R^(X) and is independently        and optionally substituted with 0-5 J^(o);    -   each R^(o) is independently H, C₁₋₆aliphatic, C₁₋₄haloaliphatic,        CO(C₁₋₄aliphatic), CO₂(C₁₋₄aliphatic), —SO₂(C₁₋₄aliphatic),        —SO₂(phenyl), phenyl, 5-6 membered heteroaryl, 5-8 membered        heterocyclyl, C₃₋₈cycloaliphatic, —C₁₋₆aliphatic-(Ph),        —C₁₋₆alkyl-(5-6 membered heteroaryl), —C₁₋₆alkyl-(5-8 membered        heterocyclyl), —C₁₋₆alkyl-(C₃₋₈cycloaliphatic); or        C₁₋₁₀alkylidene chain wherein up to 2 methylene units of the        chain are optionally replaced by O, N, or S; wherein said R^(o)        is optionally substituted with 0-6 J^(o);    -   or two R^(o), on the same substituent or different substituents,        taken together with the atom(s) to which each R^(o) group is        bound, form a 3-8 membered saturated, partially unsaturated, or        fully unsaturated monocyclic or bicyclic ring having 0-4        heteroatoms independently selected from nitrogen, oxygen, or        sulfur; wherein said ring is optionally and independently        substituted with 0-4 occurrences of halogen, NO₂, CN,        C₁₋₄aliphatic, NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, OH,        O(C₁₋₄aliphatic), CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄        aliphatic), or haloC₁₋₄aliphatic, wherein each of the R^(o)        C₁₋₄aliphatic groups is unsubstituted;    -   each J^(o) is independently halogen, NO₂, CN, C₁₋₄ aliphatic,        —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —OH, —O(C₁₋₄        aliphatic), —CO₂H, —CO₂(C₁₋₄ aliphatic), —O(haloC₁₋₄ aliphatic),        and halo(C₁₋₄ aliphatic), wherein each of the J^(o)        C₁₋₄aliphatic groups is unsubstituted.

In some embodiments of this invention, when R² is 2-pyridyl and R³ andR⁴ are H, then Q-Q¹ is not

wherein Q-Q¹ is a bicyclic ring formed by the fusion of Q¹ to Q.

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, a specified number range of atoms includes anyinteger therein. For example, a group having from 1-4 atoms could have1, 2, 3, or 4 atoms.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds.

The term “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and preferably their recovery, purification, anduse for one or more of the purposes disclosed herein. In someembodiments, a stable compound or chemically feasible compound is onethat is not substantially altered when kept at a temperature of 40° C.or less, in the absence of moisture or other chemically reactiveconditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation that has a single point ofattachment to the rest of the molecule. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, or alkynyl groups. Specific examples include, but are notlimited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl,n-butenyl, ethynyl, and tert-butyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or“cycloalkyl”) refers to a monocyclic C₃-C₈ hydrocarbon or bicyclicC₈-C₁₂ hydrocarbon that is completely saturated or that contains one ormore units of unsaturation, but which is not aromatic, that has a singlepoint of attachment to the rest of the molecule wherein any individualring in said bicyclic ring system has 3-7 members. Suitablecycloaliphatic groups include, but are not limited to, cycloalkyl andcycloalkenyl groups. Specific examples include, but are not limited to,cyclohexyl, cyclopropenyl, and cyclobutyl.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic,or tricyclic ring systems in which one or more ring members are anindependently selected heteroatom. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic”group has three to fourteen ring members in which one or more ringmembers is a heteroatom independently selected from oxygen, sulfur,nitrogen, or phosphorus, and each ring in the system contains 3 to 7ring members.

Suitable heterocycles include, but are not limited to,3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl,2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl,4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl,4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,5-imidazolidinyl, indolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and1,3-dihydro-imidazol-2-one.

Cyclic groups, (e.g. cycloaliphatic and heterocycles), can be linearlyfused, bridged, or spirocyclic.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “fully unsaturated”, when referring to a ring, means anaromatic ring.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl or alkoxy, as the case may be, substituted with oneor more halogen atoms. The terms “halogen”, “halo”, and “hal” mean F,Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”. Suitable heteroaryl rings include, but arenot limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl),2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl),triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl,benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g.,2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl,1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl,4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

The term “protecting group”, as used herein, refers to an agent used totemporarily block one or more desired reactive sites in amultifunctional compound. In certain embodiments, a protecting group hasone or more, or preferably all, of the following characteristics: a)reacts selectively in good yield to give a protected substrate that isstable to the reactions occurring at one or more of the other reactivesites; and b) is selectively removable in good yield by reagents that donot attack the regenerated functional group. Exemplary protecting groupsare detailed in Greene, T. W., Wuts, P. G in “Protective Groups inOrganic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999,the entire contents of which are hereby incorporated by reference. Theterm “nitrogen protecting group”, as used herein, refers to an agentsused to temporarily block one or more desired nitrogen reactive sites ina multifunctional compound. Preferred nitrogen protecting groups alsopossess the characteristics exemplified above, and certain exemplarynitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, ThirdEdition, John Wiley & Sons, New York: 1999, the entire contents of whichare hereby incorporated by reference.

In some embodiments, an alkyl or aliphatic chain can be optionallyinterrupted with another atom or group. This means that a methylene unitof the alkyl or aliphatic chain is optionally replaced with said otheratom or group. Examples of such atoms or groups would include, but arenot limited to, —NR—, —O—, —S—, —CO₂—, —OC(O)—, —C(O)CO—, —C(O)—,—C(O)NR—, —C(═N—CN), —NRCO—, —NRC(O)O—, —SO₂NR—, —NRSO₂—, —NRC(O)NR—,—OC(O)NR—, —NRSO₂NR—, —SO—, or —SO₂—, wherein R is defined herein.Unless otherwise specified, the optional replacements form a chemicallystable compound. Optional interruptions can occur both within the chainand at either end of the chain; i.e. both at the point of attachmentand/or also at the terminal end. Two optional replacements can also beadjacent to each other within a chain so long as it results in achemically stable compound.

Unless otherwise specified, if the replacement or interruption occurs atthe terminal end, the replacement atom is bound to an H on the terminalend. For example, if —CH₂CH₂CH₃ were optionally interrupted with —O—,the resulting compound could be —OCH₂CH₃, —CH₂OCH₃, or —CH₂CH₂OH.

Unless otherwise indicated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Additionally, unless otherwise indicated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C— or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

The following abbreviations are used:

DMF dimethylformamide

DCM dichloromethane

Ac acetyl

THF tetrahydrofuran

DMF dimethylformamide

EtOAc ethyl acetate

DMSO dimethyl sulfoxide

Et₂O diethylether

PE petroleum ether

MeCN acetonitrile

TCA trichloroacetic acid

BuLi butyllithium

ATP adenosine triphosphate

NMP N-methylpyrrolidone

m-CPBA m-chloroperoxybenzoic Acid

EtOH ethanol

MeOH methanol

Ph phenyl

Me methyl

Et ethyl

HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

BSA bovine serum albumin

DTT dithiothreitol

NMR nuclear magnetic resonance

TLC thin layer chromatography

HPLC high performance liquid chromatography

LCMS liquid chromatography-mass spectrometry

Rt retention time

In one embodiment of this invention, Q is

It should be understood that J^(Q) is a substituent on any carbon atomof the 5-membered heteroaryl ring. J^(Q) is not a substituent on thenitrogen atom. The nitrogen atoms in Q, if substituted, are onlysubstituted with H, as shown above. In some embodiments, Q¹ isoptionally substituted phenyl.

In certain embodiments, the fused bicyclic ring formed by Q and Q¹ isdescribed as Q-Q¹. In some embodiments, Q-Q¹ is

In some embodiments, Q-Q¹ is

In some embodiments, Q-Q¹ is

In some embodiments, Q-Q¹ is

In some embodiments,

-   -   each J^(Q) is independently selected from CN, halo, C₁₋₆alkyl,        C₁₋₄haloalkyl, —OR^(o), —N(R^(o))₂, —SR^(o),        —(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂,        —(C₁₋₆alkyl)-SR^(o), —(U)_(m)—(C₆₋₁₀aryl) —(U)_(m)—(5-12        membered heteroaryl), —(U)_(m)—(3-12 membered heterocyclyl),        —(U)_(m)—(C₃₋₁₀cycloaliphatic), —C(O)OR^(o), —NR^(o)COR^(o),        —COR^(o), —CON(R^(o))₂, —SO₂R^(o), and —SO₂N(R^(o))₂;    -   U is a C₁₋₁₀alkyl, wherein 0-1 methylene units are independently        replaced by, —NR^(o)—, —O—, or —S—;    -   m is 0 or 1.

In some embodiments, J^(Q) is CN, halo, C₁₋₆alkyl, C₁₋₄haloalkyl,—OR^(o), —N(R^(o))₂, —SR^(o), —NH—(C₁₋₆alkyl)-(3-8 memberedheterocyclyl), —O—(C₁₋₆alkyl)-(3-8 membered heterocyclyl), 3-8 memberedheterocyclyl, —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o), —CON(R^(o))₂,—SO₂R^(o), or —SO₂N(R^(o))₂; In some embodiments, J^(Q) is —N(R^(o))₂,OR^(o), or optionally substituted 5-8 membered heterocyclyl. In someembodiments, said 5-8 membered heterocyclyl contains 0-2 nitrogen atoms.In certain embodiments, J^(Q) is an optionally substituted groupselected from piperidinyl, piperazinyl, and pyrrolidinyl.

In some embodiments, each J^(Q) is optionally and independentlysubstituted with 0-5 R^(X); in other embodiments, 0-3 R^(X); in yetother embodiments, 0-1 R^(X).

In other embodiments of this invention, R^(X) is selected from H,methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl,t-butyl, halogen, NO₂, CN, NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂,OH, O(C₁₋₄aliphatic), CO₂H, OCF₃, CF₃, COCH₃,—(C₁₋₄alkyl)₀₋₁—O(C₁₋₄alkyl), —(C₁₋₄alkyl)₀₋₁—O (C₁₋₄alkyl)OH,—(C₁₋₄alkyl)₀₋₁—NH(C₁₋₄alkyl), —(C₁₋₄alkyl)₀₋₁—N(C₁₋₄alkyl)₂,—(C₁₋₄alkyl)₀₋₁—NH₂, and —(C₁₋₄alkyl)₀₋₁—(3-7 membered heterocyclyl).

In some embodiments, each R^(X) is optionally and independentlysubstituted with 0-5 J^(o); in some embodiments, 0-3 J^(o); in someembodiments, 0-1 J^(o).

In yet other embodiments of this invention, R^(o) is selected from H,methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl,t-butyl, COCH₃, —(C₁₋₄alkyl)-O (C₁₋₄alkyl), —(C₁₋₄alkyl)-O(C₁₋₄alkyl)OH,—(C₁₋₄alkyl)-NH(C₁₋₄alkyl), —(C₁₋₄alkyl)-N(C₁₋₄alkyl)₂,—(C₁₋₄alkyl)-NH₂, and —(C₁₋₄alkyl)₀₋₁—(3-7 membered heterocyclyl).

In some embodiments, each R^(o) is optionally and independentlysubstituted with 0-5 J^(o); in some embodiments, 0-3 J^(o); in someembodiments, 0-1 J^(o);

In some embodiments, each R³ and R⁴ is independently H. In certainembodiments, R³ and R⁴ are both H.

In another embodiment of this invention, R² is a 5-8 memberedmonocyclyl. In some embodiments, R² is C₃₋₈cycloaliphatic. In otherembodiments, R² is a 5-6 membered aryl or heteroaryl ring. In yet otherembodiments, R² is an optionally substituted 6-membered aryl or6-membered heteroaryl ring having 0-2 nitrogen atoms. In someembodiments, R² is a phenyl, pyridyl, pyrazinyl, or pyrimidyl ring. Incertain embodiments, R² is a phenyl, 3-pyridyl, 4-pyridyl, pyrazinyl,2,4-pyrimidyl, or 3,5-pyrimidyl ring.

In some embodiments, R² is optionally substituted phenyl. In otherembodiments, R² is a phenyl, 3-pyridyl, pyrazinyl, 2,4-pyrimidyl, or3,5-pyrimidyl ring.

In certain embodiments, R² is optionally substituted with 0-5 J^(R2); insome embodiments, 0-3 J^(R2); in some embodiments, 0-1 J^(R2).

In some embodiments of this invention, J^(R2) is selected from halo,C₁₋₆alkyl, C₆₋₁₀aryl, —C₁₋₆alkyl-C₆₋₁₀aryl, C₁₋₄haloalkyl, —OR^(o),—N(R^(o))₂, —SR^(o), NO₂, CN, 3-10 membered heterocyclyl,—(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o),—C(O)OR^(o), —NR^(o)COR^(o), —COR^(o), —CON(R^(o))₂, —SO₂R^(o),—SO₂N(R^(o))₂, or C₁₋₆ alkylidene chain, wherein up to three methyleneunits of the chain are independently replaced by, —NR^(o)—, —O—, —S—,—SO—, SO₂—, or —CO— in a chemically stable arrangement. In someembodiments, J^(R2) is selected from —OR^(o), —N(R^(o))₂, —SR^(o),—(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, or —(C₁₋₆alkyl)-SR^(o).

In some embodiments, each J^(R2) is independently and optionallysubstituted with 0-5 R^(X); in some embodiments, 0-3 R^(X); in someembodiments, 0-1 R^(X).

In some embodiments, the variables are as depicted in the compound ofTable 1.

Accordingly, a representative example of a compound of formula I isdepicted in Table 1: TABLE 1

I.1General Synthetic Methodology

The compounds of this invention may be prepared in general by methodssuch as those depicted in the general schemes below, and the preparativeexamples that follow.

Reagents and conditions: (a1) R²—B(OH)₂, Pd(PPh₃)₄, Na₂CO₃, toluene,ethanol, water, 90° C.; (a2) R²—Hal, Pd(PPh₃)₄, Na₂CO₃, toluene,ethanol, water, 90° C.; (b)LDA, THF, −78° C. then I₂, 0° C.; (c)Q—B(OH)₂, Pd(PPh₃)₄, Na₂CO₃, toluene, ethanol, water, 90° C.; (d) 2N HCldioxane, 100° C.

Scheme 1 above shows a general synthetic route that is used forpreparing the compounds I of this invention where Q and R² are asdescribed herein. Compounds of formula I can be prepared from2-fluoro-5-bromopyridine 1a. The formation of derivatives 2 is achievedby treating 1a with a boronic acid in the presence of palladium as acatalyst by using the Suzuki coupling methods that are well known in theart. The reaction is amenable to a variety of boronic acids R²—B(OH)₂.Alternatively, compounds of formula I can be prepared from2-fluoropyridine boronic acid or ester 1b. The formation of derivatives2 is achieved by treating 1b with a halide in the presence of palladiumas a catalyst by using methods similar to the one described inTetrahedron, 2002, 58, 14, 2885-2890. The reaction is amenable to avariety of halides R²-Hal. Deprotonation of 2 with LDA, followed byaddition of iodine, leads to the formation of 3 which can be reactedwith a aryl boronic acid in the presence of palladium as a catalyst togive compounds 4, using Suzuki coupling methods that are well known inthe art. The reaction is amenable to a variety of aryl boronic acidsQ—B(OH)₂. Deprotection of 4 in acidic conditions leads to the formationof I.

Accordingly, this invention also provides a process for preparing acompound of this invention.

One embodiment of this invention provides a process for preparing acompound of formula I:

comprising

-   -   a) coupling a compound of formula 1 with R²—A²;        wherein A¹ and A² are corresponding coupling functional groups;        to form the compound of formula 2;        wherein R² is as defined herein;    -   b) iodinating a compound of formula 2 under suitable conditions        to form a compound of formula 3;        wherein R² is as defined herein;    -   c) reacting the compound of formula 3;        wherein R² is as defined herein;        with Q—B(OH)₂ under Pd coupling conditions to form a compound of        formula 4;        wherein R² is as defined herein;    -   d) heating the compound of formula 4 under acidic conditions to        form the compound of formula I wherein Q and R² are as defined        herein.

Coupling functional groups are defined as any two groups that, in thepresence of a catalyst, are coupled together. Examples of couplingfunctional groups include, but are not limited to, —B(OH)₂ and a halogen(Suzuki coupling); —ZnBr and a halogen (Negishi coupling), and —SnBu₃and a halogen (Stille coupling). Examples of catalysts include, but arenot limited to, NiP(Ph₃)₄, Pd(II)acetate, Pd(dppf)Cl₂, tetrakis(triphenylphosphine) palladium, and bis(triphenylphosphine)palladium(II) chloride.

Another embodiment of this invention provides a process for preparing acompound of formula I:

comprising

-   -   a) Reacting a compound of formula 3        wherein R² is as defined herein;        with Q—B(OH)₂ under suitable coupling conditions to form a        compound of formula 4;        wherein R² is as defined herein;    -   b) heating the compound of formula 4 under acidic conditions to        form the compound of formula I wherein Q and R² are as defined        herein.

Suitable coupling conditions are known to those skilled in the art andinclude, but are not limited to, the use of a palladium catalyst (e.g.Pd(II)acetate, Pd(dppf)Cl₂, or PdP(Ph₃)₄), a suitable solvent (e.g. DCMor THF), and a suitable base (e.g. K₂CO₃ or Na₂CO₃).

Yet another embodiment of this invention provides a process comprising

-   -   a) coupling a compound of formula 1 with R²-A²;        wherein A¹ and A² are corresponding coupling functional groups;        to form a compound of formula 2;        wherein R² is as defined herein;    -   b) iodinating the compound of formula 2 under suitable        conditions to form a compound of formula 3;        wherein R² is as defined herein.        Pharmaceutical Compositions

As discussed above, the present invention provides compounds that areinhibitors of protein kinases, and thus the present compounds are usefulfor the treatment of diseases, disorders, and conditions including, butnot limited to an autoimmune, inflammatory, proliferative, orhyperproliferative disease or an immunologically-mediated disease.Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative or salt thereof whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a Tec family (e.g.,Tec, Btk,Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases kinase.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺ (C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersible products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar—agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Methods of Treatment

As described generally above, the compounds of the invention are usefulas inhibitors of protein kinases. In one embodiment, the compounds andcompositions of the invention are inhibitors of one or more of Tecfamily (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, and thus,without wishing to be bound by any particular theory, the compounds andcompositions are particularly useful for treating or lessening theseverity of a disease, condition, or disorder where activation of one ormore of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinaseis implicated in the disease, condition, or disorder. When activation ofTec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) is implicated in aparticular disease, condition, or disorder, the disease, condition, ordisorder may also be referred to as a “Tec family (e.g.,Tec, Btk,Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease” or disease symptom.

Accordingly, in another aspect, the present invention provides a methodfor treating or lessening the severity of a disease, condition, ordisorder where activation or one or more of Tec family (e.g.,Tec, Btk,Itk/Emt/Tsk, Bmx, Txk/Rlk) is implicated in the disease state.

In yet another aspect, a method for the treatment or lessening theseverity of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx,Txk/Rlk)-mediated diseases is provided comprising administering aneffective amount of a compound, or a pharmaceutically acceptablecomposition comprising a compound to a subject in need thereof. In someembodiments, said Tec-family-mediated disease is an Itk-mediateddisease. In certain embodiments of the present invention an “effectiveamount” of the compound or pharmaceutically acceptable composition isthat amount effective for a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx,Txk/Rlk)-mediated disease. The compounds and compositions, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx,Txk/Rlk)-mediated disease. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. The compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The term “Tec family tyrosine kinases-mediated condition”, as usedherein means any disease or other deleterious condition in which Tecfamily kinases are known to play a role. Such conditions include,without limitation, autoimmune, inflammatory, proliferative, andhyperproliferative diseases and immunologically mediated diseasesincluding rejection of transplanted organs or tissues and AcquiredImmunodeficiency Syndrome (AIDS).

For example, Tec family tyrosine kinases-mediated conditions includediseases of the respiratory tract including, without limitation,reversible obstructive airways diseases including asthma, such asbronchial, allergic, intrinsic, extrinsic and dust asthma, particularlychronic or inveterate asthma (e.g. late asthma airwayshyper-responsiveness) and bronchitis. Additionally, Tec family tyrosinekinases diseases include, without limitation, those conditionscharacterised by inflammation of the nasal mucus membrane, includingacute rhinitis, allergic, atrophic thinitis and chronic rhinitisincluding rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta,rhinitis sicca and rhinitis medicamentosa; membranous rhinitis includingcroupous, fibrinous and pseudomembranous rhinitis and scrofoulousrhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) andvasomotor rhinitis, sarcoidosis, farmer's lung and related diseases,fibroid lung and idiopathic interstitial pneumonia.

Tec family tyrosine kinases-mediated conditions also include diseases ofthe bone and joints including, without limitation, (pannus formation in)rheumatoid arthritis, seronegative spondyloarthropathis (includingankylosing spondylitis, psoriatic arthritis and Reiter's disease),Behcet's disease, Sjogren's syndrome, and systemic sclerosis.

Tec family kinases-mediated conditions also include diseases anddisorders of the skin, including, without limitation, psoriasis,systemic sclerosis, atopical dermatitis, contact dermatitis and othereczematous dermatitis, seborrhoetic dermatitis, Lichen planus,Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria,angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis,Alopecia, areata and vernal conjunctivitis.

Tec family tyrosine kinases-mediated conditions also include diseasesand disorders of the gastrointestinal tract, including, withoutlimitation, Coeliac disease, proctitis, eosinophilic gastro-enteritis,mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis,food-related allergies which have effects remote from the gut, e.g.migraine, rhinitis and eczema.

Tec family tyrosine kinases-mediated conditions also include thosediseases and disorders of other tissues and systemic disease, including,without limitation, multiple sclerosis, atherosclerosis, acquiredimmunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus,erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type Idiabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,lepromatous leprosy, sezary syndrome and idiopathic thrombocytopeniapurpura, restenosis following angioplasty, tumours (for exampleleukemia, lymphomas), artherosclerosis, and systemic lupuserythematosus.

Tec family tyrosine kinases-mediated conditions also include allograftrejection including, without limitation, acute and chronic allograftrejection following for example transplantation of kidney, heart, liver,lung, bone marrow, skin and cornea; and chronic graft versus hostdisease.

Combination Therapies

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

For example, chemotherapeutic agents or other anti-proliferative agentsmay be combined with the compounds of this invention to treatproliferative diseases and cancer. Examples of known chemotherapeuticagents include, but are not limited to, for example, other therapies oranticancer agents that may be used in combination with the inventiveanticancer agents of the present invention include surgery, radiotherapy(in but a few examples, gamma.-radiation, neutron beam radiotherapy,electron beam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes, to name a few), endocrine therapy, biologicresponse modifiers (interferons, interleukins, and tumor necrosis factor(TNF) to name a few), hyperthermia and cryotherapy, agents to attenuateany adverse effects (e.g., antiemetics), and other approvedchemotherapeutic drugs, including, but not limited to, alkylating drugs(mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan,Ifosfamide), antimetabolites (Methotrexate), purine antagonists andpyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile,Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine,Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan),antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas(Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin),enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide,and Megestrol), Gleevec™, adriamycin, dexamethasone, andcyclophosphamide. For a more comprehensive discussion of updated cancertherapies see, http://www.nci.nih.gov/, a list of the FDA approvedoncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, andThe Merck Manual, Seventeenth Ed. 1999, the entire contents of which arehereby incorporated by reference.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for Parkinson'sDisease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole,bromocriptine, pergolide, trihexephendyl, and amantadine; agents fortreating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such asalbuterol and Singulair®; agents for treating schizophrenia such aszyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agentssuch as corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

Medical Devices

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating implantable medical devices, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device.

Vascular stents, for example, have been used to overcome restenosis(re-narrowing of the vessel wall after injury). However, patients usingstents or other implantable devices risk clot formation or plateletactivation. These unwanted effects may be prevented or mitigated bypre-coating the device with a pharmaceutically acceptable compositioncomprising a kinase inhibitor. Suitable coatings and the generalpreparation of coated implantable devices are described in U.S. Pat.Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typicallybiocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

In vitro uses

The activity of a compound utilized in this invention as an inhibitor ofa Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the phosphorylation activityor ATPase activity of activated Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk,Bmx, Txk/Rlk) kinase. Alternate in vitro assays quantitate the abilityof the inhibitor to bind to a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk,Bmx, Txk/Rlk) kinase. Inhibitor binding may be measured byradiolabelling the inhibitor prior to binding, isolating theinhibitor/Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk), complexand determining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk,Bmx, Txk/Rlk) kinase bound to known radioligands.

The term “measurably inhibit”, as used herein means a measurable changein a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinaseactivity between a sample comprising said composition and a Tec family(e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase and an equivalentsample comprising a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx,Txk/Rlk) kinase in the absence of said composition.

Another aspect of the invention provides a method for modulating enzymeactivity by contacting a compound of formula I with a protein kinase. Insome embodiments, said protein kinase is a Tec family (e.g., Tec, Btk,Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase.

Biological Sample

Another aspect of the invention relates to inhibiting protein kinaseactivity in a biological sample or a patient, which method comprisesadministering to the patient, or contacting said biological sample witha compound of formula I or a composition comprising said compound. Theterm “biological sample”, as used herein, means an in vitro or an exvivo sample, and includes, without limitation, cell cultures or extractsthereof; biopsied material obtained from a mammal or extracts thereof;and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof. In some embodiments, said protein kinase is a Tecfamily (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase.

Inhibition of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)kinase activity in a biological sample is useful for a variety ofpurposes that are known to one of skill in the art. Examples of suchpurposes include, but are not limited to, blood transfusion,organ-transplantation, biological specimen storage, and biologicalassays.

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds or by thosemethods depicted in the Examples below.

EXAMPLES Example 1

3-(1H-indol-2-yl)-5-phenylpyridin-2(1H)-one I-1

Method 1

2-fluoro-5-phenylpyridine

To a solution of 5-bromo-2-fluoropyridine (2.33 g, 13.2 mmol) in toluene(100 mL) and ethanol (25 mL) were added Pd(PPh3)4 (764 mg, 0.66 mmol),phenylboronic acid (2.42 g, 19.8 mmol, 1.5 eq) and a solution of sodiumcarbonate (9.6 g, 90.7 mmol, 6.85 eq) in water (50 mL). The reactionmixture was heated to 90 C for 2 hours, allowed to cool to roomtemperature and partitioned between water and ethyl acetate. The organiclayer was dried and evaporated and the residue purified by columnchromatography (petrol/ethyl acetate gradient) to afford the titlecompound as a colorless oil (2.14 g, 93%)Method 2

2-fluoro-3-iodo-5-phenylpyridine

2.5 M n-BuLi in hexanes (460 μL, 1.15 mmol, 1.0 Eq.) was added dropwiseto a stirred solution of diisopropylamine (162 μL, 1.15 mmol, 1.0 Eq.)in anhydrous THF (20 mL) at −78° C. under nitrogen. The reaction waswarmed to 0° C. and stirred for 30 minutes. The reaction was cooled to−78° C. and a solution of 2-fluoro-5-phenyl-pyridine (200 mg, 1.15 mmol,1.0 Eq.) in anhydrous THF (5 mL) was added dropwise. The reaction wasstirred at −78° C. for 2 hours then warmed to 0° C. and stirred foranother 2 hours before warming to ambient temperature and stirring for afurther 2 hours. Saturated aqueous sodium thiosulfate (20 mL) was addedand the aqueous layer extracted with Et₂O (3×30 mL). The combinedorganic extracts were dried (MgSO₄), filtered and the solvent removed invacuo. The residue was purified by column chromatography on SiO₂,eluting with 5% Et₂O/petroleum ether to give the desired compound as awhite solid (114 mg, 0.38 mmol, 33%).Method 3

tert-butyl 2-(2-fluoro-5-phenylpyridin-3-yl)-1H-indole-1-carboxylate

Na₂CO₃ (279 mg, 2.63 mmol, 6.9 Eq.) in water (2 mL) was added to amixture of 2-fluoro-3-iodo-5-phenyl-pyridine (114 mg, 0.38 mmol, 1.0Eq.), Pd(PPh₃)₄ (44 mg, 0.04 mmol, 10 mol %) and 1-boc-indole-2-boronicacid (116 mg, 0.57 mmol, 1.5 Eq.) in toluene (5 mL) and EtOH (1 mL). Thereaction was heated at reflux under nitrogen overnight. After cooling toambient temperature the reaction mixture was diluted with water (10 mL)and extracted with EtOAc (3×20 mL). The combined organic extracts weredried (MgSO₄), filtered and the solvent removed in vacuo. The residuewas purified by column chromatography on SiO₂, eluting with 10%Et₂O/petroleum ether to give the desired compound as a white foam (113mg, 0.29 mmol, 76%).Method 4

3-(1H-indol-2-yl)-5-phenylpyridin-2(1H)-one I-1

Concentrated HCl (0.5 mL) was added dropwise to a stirred solution of2-(2-fluoro-5-phenyl-pyridin-3-yl)-indole-1-carboxylic acid tert-butylester (113 mg, 0.29 mmol, 1.0 eq.) in dioxane (6 mL) and water (2 mL).The reaction was heated at reflux overnight. The reaction was cooled toambient temperature and the solvent removed in vacuo. The crude residuewas partitioned between water (10 mL) and EtOAc (15 mL) and the aqueouslayer extracted with EtOAc (3×15 mL). The combined organic extracts weredried (MgSO₄), filtered and the solvent removed in vacuo. The residuewas purified by column chromatography on SiO₂, eluting with 50%EtOAc/petroleum ether to 100% EtOAc to 10% MeOH/DCM to give the desiredproduct as a yellow solid (25 mg, 0.09 mmol, 30%).

The characterization data for compound I-1 is summarized in Table 2below and includes HPLC, LC/MS (observed) and ¹H NMR data.

¹H NMR data is summarized in Table 2 and was found to be consistent withstructure. ¹H-NMR spectra were recorded at 400 MHz using a Bruker DPX400 instrument in deuterated DMSO, unless otherwise indicated.

LCMS samples were analyzed on a MicroMass Quattro Micro massspectrometer operated in single MS mode with electrospray ionization.Samples were introduced into the mass spectrometer using chromatography.Mobile phase for all mass spec. analyses consisted of 10 mM pH 7ammonium acetate and a 1:1 acetonitrile-methanol mixture, columngradient conditions are 5%-100% acetonitrile-methanol over 4.5 minsgradient time and 6.2 mins run time on an ACE C8 3.0×75 mm column. Flowrate is 1.0 ml/min.

As used herein, the term “Rt(min)” refers to the HPLC retention time, inminutes, associated with the compound. Unless otherwise indicated, theHPLC method utilized to obtain the reported retention time is asfollows:

-   -   Column: ACE C8 column, 4.6×150 mm    -   Gradient: 0-100% acetonitrile+methanol 60:40 (20 mM Tris        phosphate)    -   Flow rate: 1.5 mL/minute    -   Detection: 225 nm.

Compound numbers correspond to the compound numbers listed in Table 1.TABLE 2 Characterization data for selected compound of formula ICompound Rt No M + 1(obs) (min) ¹H-NMR I.1 287.5 9.7 6.99(1H, t),7.10(1H, t), 7.35(1H, t), 7.41(1H, s), 7.47(3H, t), 7.54(1H, d),7.73(2H, d), 7.75(1H, brd s), 8.46(1H, d), 11.54(1H, s), 12.28(1H, brds)

Example 2 Itk Inhibition Assay

The compounds of the present invention can be evaluated as inhibitors ofhuman Itk kinase using either a radioactivity-based orspectrophotometric assay. In general, compounds of the invention,including the compound in Table 1, are effective for the inhibition ofITK. Specifically, compound I.1 has a Ki value of <2 uM.

Itk Inhibition Assay: Radioactivity-based Assay

Assays are carried out in a mixture of 100 mM HEPES (pH 7.5), 10 mMMgCl₂, 25 mM NaCl, 0.01% BSA and 1 mM DTT. Final substrateconcentrations are 15 μM [γ-³³P]ATP (400 μCi ³³P ATP/μmol ATP, AmershamPharmacia Biotech/Sigma Chemicals) and 2 μM peptide (SAM68 proteinΔ332-443). Assays are carried out at 25° C. in the presence of 30 nMItk. An assay stock buffer solution is prepared containing all of thereagents listed above, with the exception of ATP and the test compoundof interest. 50 μL of the stock solution is placed in a 96 well platefollowed by addition of 1.5 μL of DMSO stock containing serial dilutionsof the test compound (typically starting from a final concentration of15 μM with 2-fold serial dilutions) in duplicate (final DMSOconcentration 1.5%). The plate is pre-incubated for 10 minutes at 25° C.and the reaction initiated by addition of 50 μL [γ-³³P]ATP (finalconcentration 15 μM).

The reaction is stopped after 10 minutes by the addition of 50 μL of aTCA/ATP mixture (20% TCA, 0.4 mM ATP). A Unifilter GF/C 96 well plate(Perkin Elmer Life Sciences, Cat no. 6005174) is pretreated with 50 μLMilli Q water prior to the addition of the entire reaction mixture (150μL). The plate is washed with 200 μL Milli Q water followed by 200 μL ofa TCA/ATP mixture (5% TCA, 1 mM ATP). This wash cycle is repeated afurther 2 times. After drying, 30 μL Optiphase ‘SuperMix’ liquidscintillation cocktail (Perkin Elmer) is added to the well prior toscintillation counting (1450 Microbeta Liquid Scintillation Counter,Wallac).

IC50 data are calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10 mM MgCl₂,0.1% BSA and 1 mM DTT. Final substrate concentrations in the assay are7.5 μM [γ-³³P]ATP (400 μCi ³³p ATP/μmol ATP, Amersham PharmaciaBiotech/Sigma Chemicals) and 3 μM peptide (SAM68 protein Δ332-443).Assays are carried out at 25° C. in the presence of 50 nM Itk. An assaystock buffer solution is prepared containing all of the reagents listedabove, with the exception of ATP and the test compound of interest. 50μL of the stock solution is placed in a 96 well plate followed byaddition of 2 μL of DMSO stock containing serial dilutions of the testcompound (typically starting from a final concentration of 50 μM with2-fold serial dilutions) in duplicate (final DMSO concentration 2%). Theplate is pre-incubated for 10 minutes at 25° C. and the reactioninitiated by addition of 50 μL [γ-³³P]ATP (final concentration 7.5 μM).

The reaction is stopped after 10 minutes by the addition of 100 μL 0.2Mphosphoric acid+0.01% TWEEN 20. A multiscreen phosphocellulose filter96-well plate (Millipore, Cat no. MAPHN0B50) is pretreated with 100 μL0.2M phosphoric acid+0.01% TWEEN 20 prior to the addition of 170 μL ofthe stopped assay mixture. The plate is washed with 4×200 μL 0.2Mphosphoric acid+0.01% TWEEN 20. After drying, 30 μL Optiphase ‘SuperMix’liquid scintillation cocktail (Perkin Elmer) is added to the well priorto scintillation counting (1450 Microbeta Liquid Scintillation Counter,Wallac).

Ki(app) data are calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

Itk Inhibition Assay: Spectrophotometric Assay

Compound I.1 was screened for its ability to inhibit Itk using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249).

Assays were carried out in a mixture of 20 mM MOPS (pH 7.0), 10 mMMgCl₂, 0.1% BSA, 1 mM DTT, 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase. Finalsubstrate concentrations in the assay were 100 μM ATP (Sigma Chemicals)and 3 μM peptide (Biotinylated SAM68 Δ332-443). Assays were carried outat 25° C. and in the presence of 100 nM Itk.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of ATP and the test compoundof interest. 60 μl of the stock solution was placed in a 96 well platefollowed by addition of 2 μl of DMSO stock containing serial dilutionsof the test compound (typically starting from a final concentration of15 μM). The plate was preincubated for 10 minutes at 25° C. and thereaction initiated by addition of 5 μl of ATP. Initial reaction rateswere determined with a Molecular Devices SpectraMax Plus plate readerover a 10 minute time course. IC50 and Ki data were calculated fromnon-linear regression analysis using the Prism software package(GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, SanDiego Calif., USA).

Example 3 Btk Inhibition Assay

The compounds of the present invention can be evaluated as inhibitors ofhuman Btk kinase using a radioactivity-based assay.

Btk Inhibition Assay: Radioactivity-Based Assay

Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10 MM MgCl₂,0.1% BSA and 1 mM DTT. Final substrate concentrations in the assay are50 μM [γ-³³P]ATP (200 μCi ³³P ATP/μmol ATP, Amersham Pharmacia Biotech,Amersham, UK/Sigma Chemicals) and 2 μM peptide (SAM68 Δ332-443). Assaysare carried out at 25° C. and in the presence of 25 nM Btk. An assaystock buffer solution is prepared containing all of the reagents listedabove, with the exception of the peptide and the test compound ofinterest. 75 μL of the stock solution is placed in a 96 well platefollowed by addition of 2 μL of DMSO stock containing serial dilutionsof the test compound (typically starting from a final concentration of15 μM) in duplicate (final DMSO concentration 2%). The plate ispreincubated for 15 minutes at 25° C. and the reaction initiated byaddition of 25 μL peptide (final concentration 2 μM). Background countsare determined by the addition of 100 μL 0.2M phosphoric acid+0.01%TWEEN to control wells containing assay stock buffer and DMSO prior toinitiation with peptide.

The reaction is stopped after 10 minutes by the addition of 100 μL 0.2Mphosphoric acid+0.01% TWEEN. A multiscreen phosphocellulose filter96-well plate (Millipore, Cat no. MAPHN0B50) is pretreated with 100 μL0.2M phosphoric acid+0.01% TWEEN 20 prior to the addition of 170 μL ofthe stopped assay mixture. The plate is washed with 4×200 μL 0.2Mphosphoric acid+0.01% TWEEN 20. After drying, 30 μL Optiphase ‘SuperMix’liquid scintillation cocktail (Perkin Elmer) is added to the well priorto scintillation counting (1450 Microbeta Liquid Scintillation Counter,Wallac).

After removing mean background values for all of the data points,Ki(app) data are calculated from non-linear regression analysis usingthe Prism software package (GraphPad Prism version 3.0cx for Macintosh,GraphPad Software, San Diego Calif., USA).

Example 4 RLK Inhibition Assay

Compounds are screened for their ability to inhibit Rlk using a standardcoupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assaysare carried out in a mixture of 20 mM MOPS (pH 7.0), 10 mM MgCl2, 0.1%BSA and 1 mM DTT. Final substrate concentrations in the assay are 100 μMATP (Sigma Chemicals) and 10 μM peptide (Poly Glu:Tyr 4:1). Assays arecarried out at 30° C. and in the presence of 40 nM Rlk. Finalconcentrations of the components of the coupled enzyme system are 2.5 mMphosphoenolpyruvate, 300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/mllactate dehydrogenase.

An assay stock buffer solution is prepared containing all of thereagents listed above, with the exception of ATP and the test compoundof interest. 60 μl of the stock solution is placed in a 96 well platefollowed by addition of 2 μl of DMSO stock containing serial dilutionsof the test compound (typically starting from a final concentration of7.5 μM). The plate is preincubated for 10 minutes at 30° C. and thereaction initiated by addition of 5 μl of ATP. Initial reaction ratesare determined with a Molecular Devices SpectraMax Plus plate readerover a 10 minute time course. IC50 and Ki data are calculated fromnon-linear regression analysis using the Prism software package(GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, SanDiego Calif., USA).

In general, compounds of the invention are effective for the inhibitionof RLK.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds, methods, and processes of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than by thespecific embodiments that have been represented by way of exampleherein.

1. A compound of formula I:

or a pharmaceutically accepted salt thereof, wherein R² is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially msaturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R² is optionally substituted with 0-5J^(R2); each R³ and R⁴ is independently H, halogen, or C₁₋₄ aliphatic optionally substituted with 0-5 occurrences of halogen, OH, OCH₃, OCF₃, NO₂, NH₂, CN, NHCH₃, SCH₃, N(CH₃)₂, or C₁₋₂aliphatic optionally substituted 0-5 times with F; Q is 5-membered heteroaryl containing 1-4 nitrogen atoms, wherein one of the nitrogen atoms is NH; each Q is optionally substituted with 0-3 J^(Q) and is optionally fused to ring Q¹; Q¹ is a 5-6 membered aryl or heteroaryl ring containing up to 3 heteroatoms selected from O, N, and S; each Q¹ is optionally substituted with 0-5 J^(Q); J^(R2) and J^(Q) are each independently halogen, —NO₂, —CN, C₁₋₆ aliphatic, C₆₋₁₀aryl, —C₁₋₆alkyl-(C₆₋₁₀aryl), 5-12 membered heteroaryl, —C₁₋₆alkyl-(5-12 membered heteroaryl), 3-12 membered heterocyclyl, —C₁₋₆alkyl-(3-12 membered heterocyclyl), C₃₋₁₀cycloaliphatic, —C₁₋₆alkyl-(C₃₋₁₀cycloaliphatic), —OR^(o), —SR^(o), —N(R^(o))₂, —(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o), —NR^(o)C(O)R^(o), —NR^(o)C(S)R^(o), —NR^(o)C(O)N(R^(o))₂, —NR^(o)C(S)N(R^(o))₂, —NR^(o)CO₂R^(o), —NR^(o)NR^(o)C(O)R^(o), —NR^(o)NR^(o)C(O)N(R^(o))₂, —NR^(o)NR^(o)CO₂R^(o), —C(O)C(O)R^(o), —C(O)CH₂C(O)R^(o), —CO₂R^(o), —C(O)R^(o), —C(S)R^(o), —C(O)N(R^(o))₂, —C(S)N(R^(o))₂, —OC(O)N(R^(o))₂, —OC(O)R^(o), —C(O)N(OR^(o))R^(o), —C(NOR^(o))R^(o), —S(O)₂R^(o), —S(O)₃R^(o), —SO₂N(R^(o))₂, —S(O)R^(o), —NR^(o)SO₂N(R^(o))₂, —NR^(o)SO₂R^(o), —N(OR^(o))R^(o), —C(═NH)-N(R^(o))₂, —P(O)₂R^(o), —PO(R^(o))₂, —OPO(R^(o))₂, ═O, ═S, ═NNHR^(o), ═NN(R^(o))₂, ═NNHC(O)R^(o), ═NNHCO₂(C₁₋₆alkyl), ═NNHSO₂(C₁₋₆alkyl), ═NOH, ═NR^(o); or C₁₋₁₀ alkylidene chain, wherein up to three methylene units of the chain are independently replaced by —NR^(o)—, —O—, —S—, —SO—, SO₂—, or —CO—; wherein each J^(R2) and J^(Q) is independently and optionally substituted with 0-5 R^(X); each R^(X) is independently H, halogen, NO₂, CN, NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, OH, O(C₁₋₄aliphatic), O(C₁₋₄haloaliphatic), CO(C₁₋₄aliphatic), CO₂H, CO₂(C₁₋₄aliphatic), C₁₋₆aliphatic, C₁₋₄haloaliphatic, phenyl, —O(Ph), 5-6 membered heteroaryl, C₃₋₈cycloaliphatic, 5-8 membered heterocyclyl, —C₁₋₆aliphatic-(Ph), —C₁₋₆alkyl-(5-6 membered heteroaryl), —C₁₋₆alkyl-(C₃₋₈cycloaliphatic), —C₁₋₆alkyl-(5-8 membered heterocyclyl), or C₁₋₁₀alkylidene chain wherein up to 2 methylene units of the chain are optionally replaced by O, N, or S; wherein each R^(X) and is independently and optionally substituted with 0-5 J^(o); each R^(o) is independently H, C₁₋₆aliphatic, C₁₋₄haloaliphatic, CO(C₁₋₄aliphatic), CO₂(C₁₋₄aliphatic), —SO₂(C₁₋₄aliphatic), —SO₂(phenyl), phenyl, 5-6 membered heteroaryl, 5-8 membered heterocyclyl, C₃₋₈cycloaliphatic, —C₁₋₆aliphatic-(Ph), —C₁₋₆alkyl-(5-6 membered heteroaryl), —C₁₋₆alkyl-(5-8 membered heterocyclyl), —C₁₋₆alkyl-(C₃₋₈cycloaliphatic); or C₁₋₁₀alkylidene chain wherein up to 2 methylene units of the chain are optionally replaced by O, N, or S; wherein said R^(o) is optionally substituted with 0-6 J^(o); or two R^(o), on the same substituent or different substituents, taken together with the atom(s) to which each R^(o) group is bound, form a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said ring is optionally and independently substituted with 0-4 occurrences of halogen, NO₂, CN, C₁₋₄aliphatic, NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, OH, O(C₁₋₄aliphatic), CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or haloC₁₋₄aliphatic, wherein each of the R^(o) C₁₋₄aliphatic groups is unsubstituted; each J^(o) is independently halogen, NO₂, CN, C₁₋₄ aliphatic, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —OH, —O(C₁₋₄ aliphatic), —CO₂H, —CO₂(C₁₋₄ aliphatic), —O(haloC₁₋₄ aliphatic), and halo(C₁₋₄ aliphatic), wherein each of the J^(o) C₁₋₄aliphatic groups is unsubstituted.
 2. The compound according to claim 1, wherein when R² is 2-pyridyl and R³ and R⁴ are H; Q-Q¹ is not

wherein Q-Q¹ is a bicyclic ring formed by the fusion of Q¹ to Q.
 3. The compound according to claim 1 or claim 2, wherein Q is


4. The compound according to claim 1 or claim 2, wherein Q¹ is phenyl optionally substituted with 0-5 J^(Q).
 5. The compound according to claim 4, wherein Q-Q¹ is


6. The compound according to claim 5, wherein Q-Q¹ is substituted with up to 3 J^(Q) groups wherein each J^(Q) is independently selected from CN, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, —OR^(o), —N(R^(o))₂, —SR^(o), —(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o), C₆₋₁₀aryl, —C₁₋₆alkyl-(C₆₋₁₀aryl), 5-12 membered heteroaryl, —C₁₋₆alkyl-(5-12 membered heteroaryl), 3-12 membered heterocyclyl, —C₁₋₆alkyl-(3-12-membered heterocyclyl), C₃₋₁₀cycloaliphatic, —C₁₋₆alkyl-(C₃₋₁₀cycloaliphatic), —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o), —CON(R^(o))₂, —SO₂R^(o), or —SO₂N(R^(o))₂;
 7. The compound according to claim 6, wherein each J^(Q) is CN, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, —OR^(o), —N(R^(o))₂, —SR^(o), 3-8 membered heterocyclyl, —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o), —CON(R^(o)), —SO₂R^(o), or —SO₂N(R^(o))₂; wherein each J^(Q) is optionally and independently substituted witlh (0-5 R^(X).
 8. The compound according to claim 7, wherein J^(Q) is —N(R^(o))₂, OR^(o), or a 5-8 membered heterocyclyl optionally substituted with 0-5 R^(X).
 9. The compound according to claim 8, wherein J^(Q) is a group selected from piperidinyl, piperazinyl, and pyrrolidinyl wherein said group is optionally substituted with 0-5 R^(X).
 10. The compound according to claim 1 or claim 2, wherein R^(X) is selected from H, metlyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, halogen, NO₂, CN, NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, OH, O(C₁₋₄aliphatic), CO₂H, OCF₃, CF₃, COCH₃, —(C₁₋₄alkyl)₀₋₁—O(C₁₋₄alkyl), —(C₁₋₄alkyl)₀₋₁—O(C₁₋₄alkyl)OH, —(C₁₋₄alkyl)₀₋₁—NH(C₁₋₄alkyl), —(C₁₋₄alkyl)₀₋₁—N(C₁₋₄alkyl)₂, —(C₁₋₄alkyl)₀₋₁—NH₂, and —(C₁₋₄alkyl)₀₋₁-(3-7 membered heterocyclyl).
 11. The compound according to claim 1 or claim 2, wherein R^(o) is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, COCH₃, —(C₁₋₄alkyl) —O(C₁₋₄alkyl), —(C₁₋₄alkyl)-O(C₁₋₄alkyl)OH, —(C₁₋₄alkyl)-NH(C₁₋₄alkyl), —(C₁₋₄alkyl)-N(C₁₋₄alkyl)₂, —(C₁₋₄alkyl)-NH₂, and —(C₁₋₄alkyl)₀₋₁(3-7 membered heterocyclyl).
 12. The compound according to claim 1 or claim 2, wherein each R³ and R⁴ is independently H.
 13. The compound according to claim 12, wherein R³ and R⁴ are both H.
 14. The compound according to claim 1 or claim 2, wherein R² is 5-8 membered monocyclyl optionally substituted with up to five J^(R2).
 15. The compound according to claim 14, wherein R² is C₃₋₈cycloaliphatic optionally substituted with up to five J^(R2).
 16. The compound according to claim 14, wherein R² is a 5-6 membered aryl or heteroaryl ring, wherein said ring is optionally substituted with up to five J^(R2).
 17. The compound according to claim 16, wherein R² is an optionally substituted 6-membered aryl or 6-membered heteroaryl ring having 0-2 nitrogen atoms, wherein said ring is optionally substituted with up to five J^(R2).
 18. The compound according to claim 17, wherein R² is a phenyl, pyridyl, pyrazinyl, or pyrimidyl ring, wherein said ring is optionally substituted with up to five J^(R2).
 19. The compound according to claim 18, wherein R² is a phenyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2,4-pyrimidyl, or 3,5-pyrimidyl ring, wherein said ring is optionally substituted with up to five J^(R2).
 20. The compound according to claim 14, wherein each J^(R2) is selected from halo, C₁₋₆alkyl, C₆₋₁₀aryl, —C₁₋₆alkyl-C₆₋₁₀aryl, C₁₋₄haloalkyl, —OR^(o), —N(R^(o))₂, —SR^(o), NO₂, CN, 3-10 membered -heterocyclyl, —(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o), —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o), —CON(R^(o))₂, —SO₂R^(o), —SO₂N(R^(o))₂, or C₁₋₆ alkylidene chain, wherein up to three methylene units of the chain are independently replaced by, —NR^(o)—, —O—, —S—, —SO—, SO₂—, or —CO— in a chemically stable arrangement; each J^(R2) is independently and optionally substituted with 0-5 R^(X).
 21. The compound according to claim 20, wherein each J^(R2) is selected from —OR^(o), —N(R^(o))₂, —SR^(o), —(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, or —(C₁₋₆alkyl)-SR^(o); wherein each J^(R2) is independently and optionally substituted with 0-5 R^(X).
 22. The compound according to claim 1 selected from the following:


23. A composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
 24. A method of inhibiting protein kinase activity in a patient comprising administering to said patient a compound of claim
 1. 25. A method of inhibiting protein kinase activity in a biological sample comprising contacting said biological sample with a compound of claim
 1. 26. A method of inhibiting Tec family (Tcec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase activity in a patient comprising administering to said patient a compound of claim
 1. 27. A method of inhibiting Tec family (Tec, Btk, Itk Emt/Tsk, Bmx, Txk/Rlk) kinase activity in a biological sample comprising contacting said biological sample with a compound of claim
 1. 28. A method of inhibiting Itk kinase activity in a patient comprising administering to said patient a compound of claim
 1. 29. A method of inhibiting Itk kinase activity in a biological sample comprising contacting said biological sample with a compound of claim
 1. 30. A method of treating an autoimmune, inflammatory, proliferative, hyperproliferative or immunologically-mediated disease comprising administering to a patient in need thereof a compound of claim
 1. 31. The method of claim 30, comprising the further step of administering to said patient an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease, rejection of transplanted organs or tissues, and Acquired Immunodeficiency Syndrome (AIDS), wherein: said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
 32. A method of treating asthma, acute rhinitis, allergic, atrophic rhinitis, chronic rhinitis, membranous rhinitis;, seasonal rhinitis, sarcoidosis, farmer's lung, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathis, ankylosing spondylitis, psoriatic arthritis, Reiter's disease, Behcet's disease, Sjogren's syndrome, systetnic sclerosis, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullotis Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, areata vernal conjunctivitis, Coeliaic disease, proctitis, eosinophilic gastroenteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food-related allergies, multiple sclerosis, artherosclerosis. acquired immunodeficiency syndrome (AIDS), lupus erythernatosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia purpura, restenosis following angioplasty, tumours, artherosclerosis, systemic lupus erythematosus, allograft rejection, acute and chronic allograft rejection following transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; or chronic graft versus host disease comprising administering to a patient in need thereof a compound of claim
 1. 33. A process for preparing a compound of formula I:

comprising a) reacting a compound of formula 3

wherein R² is as defined according to claim 1; with Q-B(OH)₂ under suitable coupling conditions to form a compound of formula 4;

wherein R² is as defined according to claim 1; b) heating the compound of formula 4 under acidic conditions to form the compound of formula I wherein Q and R² are as defined according to claim
 1. 34. The process of claim 33, wherein the compound of formula 3 is prepared, comprising b) coupling a compound of formula 1 with R²-A²;

wherein A¹ and A² are corresponding coupling functional groups; to form a compound of formula 2;

wherein R² is as defined according to claim 1; c) iodinating the compound of formula 2 under suitable conditions to form a compound of formula 3;

wherein R² is as defined according to claim
 1. 35. A compound of formula I′

or a pharmaceutically accepted salt thereof, wherein R² is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R² is optionally substituted with 0-5 J^(R2); J^(R2) is halogen, —NO₂, —CN, C₁₋₆ aliphatic, C₆₋₁₀aryl, —C₁₋₆alkyl-(C₆₋₁₀aryl), 5-12 membered heteroaryl, —C₁₋₆alkyl-(5-12 membered heteroaryl), 3-12 membered heterocyclyl, —C₁₋₆alkyl-(3-12 membered heterocyclyl), C₃₋₁₀cycloaliphatic, —C₁₋₆alkyl-(C₃₋₁₀cycloaliphatic), —OR^(o), —SR^(o), —N(R^(o))₂, —(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o), —NR^(o)C(O)R^(o), —NR^(o)C(S)R^(o), —NR^(o)C(O)N(R^(o))₂, —NR^(o)C(S)N(R^(o))₂, —NR^(o)CO₂R^(o), —NR^(o)NR^(o)C(O)R^(o), —NR^(o)NR^(o)C(O)N(R^(o))₂, —NR^(o)NR^(o)CO₂R^(o), —C(O)C(O)R^(o), —C(O)CH₂C(O)R^(o), —CO₂R^(o), —C(O)R^(o), —C(S)R^(o), —C(O)N(R^(o))₂, —C(S)N(R^(o))₂, —OC(O)N(R^(o))₂, —OC(O)R^(o), —C(O)N(OR^(o))R^(o), —C(NOR^(o))R^(o), —S(O)₂R^(o), —S(O)₃R^(o), —SO₂N(R^(o))₂, —S(O)R^(o), —NR^(o)SO₂N(R^(o))₂, —NR^(o)SO₂R^(o), —N(OR^(o))R^(o), —C(═NH)-N(R^(o))₂, —P(O)₂R^(o), —PO(R^(o))₂, —OPO(R^(o))₂, ═O, ═S, ═NNHR^(o), ═NN(R^(o))₂, ═NNHC(O)R^(o), ═NNHCO₂(C₁₋₆alkyl), ═NNHSO₂(C₁₋₆alkyl), ═NOH, ═NR^(o); or C₁₋₁₀ alkylidene chain, wherein up to three methylene units of the chain are independently replaced by —NR^(o)—, —O—, —S—, —SO—, SO₂—, or —CO—; each R³ and R⁴ is independently H, halogen, or C₁₋₄ aliphatic optionally substituted with 0-5 occurrences of halogen, OH, OCH₃, OCF₃, NO₂, NH₂, CN, NHCH₃, SCH₃, N(CH₃)₂, or C₁₋₂aliphatic optionally substituted 0-5 times with F; Q-Q¹ is selected from

Q-Q¹ is substituted with up to 3 J^(Q) groups wherein each J^(Q) is independently selected from CN, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, —OR^(o), —N(R^(o))₂, —SR^(o), —(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o), —(U)_(m)-(C₆₋₁₀aryl), —(U)_(m)-(5-12 membered heteroaryl), —(U)_(m)-(3-12 membered heterocyclyl), —(U)_(m)-(C₃₋₁₀cycloaliphatic), —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o), —CON(R^(o))₂, —SO₂R^(o), and —SO₂N(R^(o))₂; U is a C₁₋₁₀alkyl, wherein 0-1 methylene units are independently replaced by, —NR^(o), —O—, or —S—; m is 0 or 1; each J^(Q) and J^(R2) is independently and optionally substituted with 0-5 R^(X); each R^(X) is independently H, halogen, NO₂, CN, NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, OH, O(C₁₋₄aliphatic), O(C₁₋₄haloaliphatic), CO(C₁₋₄aliphatic), CO₂H, CO₂(C₁₋₄aliphatic), C₁₋₆aliphatic, C₁₋₄haloaliphatic, phenyl, —O(Ph), 5-6 mernbered heteroaryl, C₃₋₈cycloaliphatic, 5-8 membered heterocyclyl, —C₁₋₆aliphatic-(Ph), —C₁₋₆alkyl-(5-6 membered heteroaryl), —C₁₋₆alkyl-(C₃₋₈cycloaliphatic), —C₁₋₆alkyl-(5-8 membered heterocyclyl), or C₁₋₁₀alkylidene chain wherein up to 2 methylene units of the chain are optionally replaced by O, N, or S; wherein each R^(X) and is independently and optionally substituted with 0-5 J^(o); each R^(o) is independently H, C₁₋₆aliphatic, C₁₋₄haloaliphatic, CO(C₁₋₄aliphatic), CO₂(C₁₋₄aliphatic), —SO₂(C₁₋₄aliphatic), —SO₂(phenyl), phenyl, 5-6 membered heteroaryl, 5-8 membered heterocyclyl, C₃₋₈cycloaliphatic, —C₁₋₆aliphatic-(Ph), —C₁₋₆alkyl-(5-6 membered heteroaryl), —C₁₋₆alkyl-(5-8 membered heterocyclyl), —C₁₋₆alkyl-(C₃₋₈cycloaliphatic); or C₁₋₁₀alkylidene chain wherein up to 2 methylene units of the chain are optionally replaced by O, N, or S; wherein said R^(o) is optionally substituted with 0-6 J^(o); or two R^(o), on the same substituent or different substituents, taken together with the atom(s) to which each R^(o) group is bound, form a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said ring is optionally and independently substituted with 0-4 occurrences of halogen, NO₂, CN, C₁₋₄aliphatic, NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, OH, O(C₁₋₄aliphatic), CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or haloC₁₋₄aliphatic, wherein each of the R^(o) C₁₋₄aliphatic groups is unsubstituted; each J^(o) is independently halogen, NO₂, CN, C₁₋₄aliphatic, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —OH, —O(C₁₋₄ aliphatic), —CO₂H, —CO₂(C₁₋₄ aliphatic), —O(haloC₁₋₄aliphatic), and halo(C₁₋₄ aliphatic), wherein each of the J^(o) C₁₋₄aliphatic groups is unsubstituted.
 36. The compound according to claim 35, wherein each J^(Q) is CN, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, —OR^(o), —N(R^(o))₂, —SR^(o), —NH-(C₁₋₆alkyl)-(3-8 membered heterocyclyl), —O—, (C₁₋₆alkyl)-(3-8 membered heterocyclyl), 3-8 membered heterocyclyl, —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o), —CON(R^(o))₂, —SO₂R^(o), or —SO₂N(R^(o))₂; wherein each J^(Q) is optionally and independently substituted with 0-5 R^(X). 